1,3,5-triazines

ABSTRACT

TRIAZINES OF FORMULA:   2-(H2N-),4-(R1-N(-R2)-),6-(R-CH(-OH)-)-S-TRIAZINE   WHEREIN R IS HYDROGEN, AN ALKYL RADICAL, A METHYLENEDIOXYPHENYL RADICAL OR A PHENYL RADICAL OPTIONALLY MONO-, DI- OR TRISUBSTITUTED WITH HALOGEN ATOMS, ALKYL, HALOALKYL OR ALKOXY RADICALS, AND R1 AND R2 ARE HYDROGEN, AND ALKYL, ALKENYL, CYCLOALKYL, DIALKYLAMINOALKYL, PIPERIDINOALKYL OR MORPHOLINOALKYL RADICAL, ONE OF SUBSTITUENTS R1 AND R2 BEING OTHER THAN HYDROGEN OR AN ALKYL RADICAL WHEN THE OTHER IS ITSELF HYDROGEN OR AN ALKYL RADICAL, OR R1 AND R2, TOGETHER WITH THE NITROGEN ATOM TO WHICH THEY ARE ATTACHED, FORM A HETEROCYCLE OR A C-ALKYLSUBSTITUTED HETEROCYCLE INCLUDING, AS SECOND HETEROATOM, A NITROGEN ATOM WHICH CARRIES AN ALKYL, ALKENYL, HYDROXYALKYL, PHENYL OR SUBSTITUTED PHENYL RADICAL, AND THEIR SALTS HAVE AN ACTIVITY ON THE CENTRAL NERVOUS SYSTEM.

"United States Patent Oflice 3,703,514 Patented Nov. 21, 1972 Int. Cl. C0711 55/20 U.S. Cl. 260-249.9 3 Claims ABSTRACT OF THE DISCLOSURE Triazines of formula:

wherein R is hydrogen, an alkyl radical, a methylenedioxyphenyl radical or a phenyl radical optionally mono-, dior trisubstituted with halogen atoms, alkyl, haloalkyl or alkoxy radicals, and R and R are hydrogen, an alkyl, alkenyl, cycloalkyl, dialkylaminoalkyl, piperidinoalkyl or morpholinoalkyl radical, one of substituents R and 'R being other than hydrogen or an alkyl radical when the other is itself hydrogen or an alkyl radical, or R and R together with the nitrogen atom to which they are attached, form a heterocycle or a C-alkylsubstituted heterocycle including, as second heteroatom, a nitrogen atom which carries an alkyl, alkenyl, hydroxyalkyl, phenyl or substituted phenyl radical, and their salts, have an activity on the central nervous system.

The present invention relates to new triazines active, in particular, on the central nervous system, of formula:

in which R is hydrogen, an alkyl radical, a methylenedioxyphenyl radical or a phenyl radical optionally mono-, dior trisubstituted with halogen atoms, alkyl, haloalkyl or alkoxy radicals, and R and R are hydrogen, an alkyl, alkenyl, cycloalkyl, dialkylaminoalkyl, piperidinoalkyl or morpholinoalkyl radical, one of the substituents R and R being other than hydrogen or an alkyl radical when the other is itself hydrogen or an alkyl radical, or R and R together with the nitrogen atom to which they are attached, form a heterocycle optionally C-alkylsubstituted, including, as second heteroatom, a nitrogen atom which carries an alkyl, alkenyl, hydroxyalkyl, phenyl or substituted phenyl radical and their salts.

Preferably, the alkylsubstituted, alkenyl and alkoxy radicals included within the above definition are lower radicals.

Similarly, the heterocycle formed by R and R together with the nitrogen atom to which they are attached is advantageously a 5-, 6- or 7-membered ring.

It will be noted that compounds (I) may exist in tautomeric forms resulting from the conversion of the amino form of the substituents of the triazine nucleus to the imino form. On the other hand, the carbon atom of compounds (I) carrying substituent R is asymmetrical and compounds (I) may thus exist under optically active or racemic forms. These various forms of compounds I are included within the scope of the invention.

Such triazines were found to have interesting therapeutical properties for the central nervous system; in particular, they are anxiolytics, antidepressives, stimulants, antihallucinatory, anti-tremorine agents and also cardio-respiratory stimulants, and the invention relates also to a therapeutical composition comprising a therapeutically active amount of a triazine of formula (I) in admixture with a therapeutically acceptable vehicle.

Moreover, these thiazines can be used as weed-killers.

The invention relates also to a process for the preparation of these new triazines, comprising reacting an a-hydroxy-carboxylic acid of formula:

0H 0 (II) with a diguanide of formula:

R1 HzNONH-CN I IH IUIH R (III) R, R and R having the above-defined meanings, and removing the resulting triazine from the reaction medium, as the free base or as a salt.

To carry out the process for the preparation of triazines according to the invention, the u-hydroxy-carboxylic acid (II) may be used as the free acid or in another reactive form. For example, good results were obtained with the anhydrides, acid halides, esters, amides or hydrazides corresponding to acids of formula (II).

The reaction is carried out by heating the reagents at a temperature below C., in the absence of solvent and of catalyst. It is, however, promoted by the presence of alkaline catalysts. In this case, diguanide (III) is advantageously introduced as a salt, particularly as a hydrohalide, for example as a hydrochloride, dihydrochloride, hydrobromide, dihydrobromide, etc., which hydrohalide is preferably treated in situ with an alkaline agent, preferably with an alkali metal alkoxide such as sodium methoxide, to release the diguanide so that, after such release, there will remain a sodium methoxide equivalent useful as catalyst.

It is only after such release that the stoichiometric amount of the desired a-hydroxy-carboxylic acid or derivative thereof will be added.

The reaction is then generally carried out in alcohol medium, at room temperature, during 2-48 hours, or by refluxing the mixture during /2 hour, and the reaction mixture is then treated with water to separate the resulting triazine. The latter precipitates out immediately or after several hours, and it is then dried and recrystallized.

It may be found advantageous to extract the triazine from the reaction medium using a suitable solvent such as methylene chloride. The solvent is then evaporated and the triazine is recrystallized from a suitable solvent, such as acetonitrile, alcohols, ketones, water or dimethylformamide;

Some diguanides (III) are new compounds. Said new diguanides are those of formula:

alkyl radical or R and R together with the nitrogen atom to which they attached, form a heterocycle optionally C-alkylsubstituted, including, as second heteroatom, a nitrogen atom which carries an alkenyl, hydroxyalkyl- 4. The characteristics of the above diguanides and of other diguanides prepared in a similar manner are given in Table 1 below.

TABLE I Melting point, 0., measured with Thieles R R N R 11 Form tubo Dicthylaminocthyl H 2 H01 171- 173 Diethylarninopropyl i 225 DiethylaminopropyL 7 Dimethylaminoisoprom 1 236-237 Dibutylaminopropyl 1 132-134 Dibutylaminoethyl s 114-116 Dipropylaminopropyl 106408 PcrhydroazepinopropyL I 103-105 Dimethylamlnoethyl. 254 Do 179-181 DlcthylaminoethyL 104-105 Dirnethylaminopropyl "down": n (I) Dicthylaminoethyl ISOPIODyI.{4-propyl-piperazinyl 2 HBr 282-2?! H 4-l1ydroxyethyl-piperaziny g Pl 'd' 0 th 1 pen m e y 1 109-110 -1-phcny -piperaziny Mmpmmpmpy] H 4-(4ehlor0pl1cnyl)-piperazlnyl 3 H01 1 201-103 4-isopropyl-pipcrazlny1 2 H13: 218-220 4-rncthyl-pcrl1ydro-l,-t-dlazepinyl 2 HBr 215-217 1 Base. I Decomposes.

phenyl or substituted phenyl or alkyl radical, said alkyl radical being other than methyl when the heterocycle is the piperazinyl group.

The alkyl radicals included within the above definition are preferably lower radicals.

These new diguanides (IV), useful in the synthesis of triazines (I) are also included within the scope of the invention. Moreover, it should be noted that said diguanides possess per se therapeutically valuable antidiabetic, anti-inflammatory and anticholinergic properties.

To prepare biguanides (IV) an hydrohalide of an amine of formula:

a HN wherein R and R have the above defined meanings, is reacted with cyano-guanidine:

NII-.(|]NHCEN This reaction is generally carried out under dry conditions, as a melt, or in a solvent such as butanol, Cellosolve, and the like.

Two examples of preparation of diguanides (IV) will be given below for illustration purposes.

(A) l-diguanyl-4-n-propyl piperazine Into a flask are charged 21 g. of cyanoguanidine and 400 ml. of butanol. The mixture is heated to refluxing temperature and 72.5 g. of N-n-propyl piperazine di-hydrobromide are added thereto portionwise, over one hour. Refluxing is maintained during five hours. The product precipitates out on cooling. It is recrystallized from ethanol at 95 C. 72 g. of di-hydrobromide are obtained, melting at 232234 C. using Thieles tube.

Analysis.Calculated (percent): Br, 42.72; N, 22.46. Found (percent): Br, 42.74; N, 22.53.

(B) 1-[2-diethylamino)ethyl1-diguanide The following examples illustrate the preparation of triazines (I), prepared from diguanides (IV) as defined above or from other diguanides within the scope of Formula III.

EXAMPLE 1 Z-amino-4-a-hydroxyheptyl-6- (4-methyl)-piperazinyl- 1,3,5-triazine Into a flask are charged 51.5 g. of 1-diguanyl-4-rnethyl piperazine (ii-hydrochloride (0.2 M.), 140 ml. of methanol and 300 ml. of a 2 N methanol solution of sodium methoxide. After stirring for a few minutes, 37.6 g. of ethyl a-hydroxycaprylate (0.2 M.) dissolved in 20 ml. of methanol are added thereto. The reaction mixture is stirred during 5 hours, and is then allowed to rest during 48 hours, and is then poured over 400 ml. of distilled water; dissolution is thereby obtained. After extracting with methylene chloride, the extracts are washed with water and dried, and the solvent is then removed. The resulting yellow oil is taken up into 100 ml. of absolute ethanol and isopropanol in hydrochloric acid solution is added to pH 2. After diluting with absolute ethanol, the resulting material is filtered and recrystallized from 500 ml. of absolute ethanol. 15 g. of di-hydrochloride, which decomposes at about 270 C., are thus obtained, the decomposition temperature being determined using Thieles tube.

AnaIysis.Calculated (percent): C, 47.24; H, 7.87; O, 4.20; N, 22.05. Found (percent): 47.47; H, 8.08; O, 3.79; N, 21.89. Melting point of the base: 82 C.

The NMR spectrum is consistent with the structure.

EXAMPLE 2 2-amino-4-a-hydroxy( 3 ',4-rnethylenedioxy)-benzyl- 6-(4-n-propyl -piperazinyl-l ,3,5-triazine Into a flask are charged 187 g. of 1-diguanyl-4-n-propyl-piperazine di-hydrobromide (0.05 M), 300 ml. of methanol and 750 ml. of a 2 N sodium methoxide solution in methanol. After stirring for a few minutes, 112 g. of ethyl 3,4-methylenedioxy-mandelate dissolved in ml. of methanol are added thereto. The reaction mixture is stirred during 4 hours and is then allowed to rest during 24 hours, after which 100 ml. of distilled Water are then added thereto; a gum which sets within 3 hours precipitates out. The product is washed with water, dried and recrystallized from acetonitrile, to give 65 g. of base melting at l48150 C. using Thieles tube.

Analysis.Calculated (percent): C, 58.05; H, 6.50; O, 12.89; N, 22.57. Found (percent): C, 58.10; H, 6.72; O, 12.91; N, 22.72.

The NMR spectrum is consistent with the structure.

EXAMPLE 3 2-amino-4-diethylaminoethylamino-6-a-hydroxybenzyl-1,3,5-triazine Into a flask are charged 136 g. of l-diethylaminoethyldiguanide di-hydrochloride (0.5 M), 300 ml. of methanol and 750 ml. of a 2 N solution of sodium methoxide in methanol. The reaction mixture is stirred during a few minutes and 90 g. of ethyl mandelate dissolved in 100 ml. of methanol are then added thereto. The reaction mixture is stirred during 4 hours and is then allowed to rest during 24 hours after which is it again stirred during 4 hours and 100 ml; of distilled water are added thereto; complete dissolution is obtained. After extracting with 3 X 500 ml. of methylene chloride, the extracts are washed with water and dried, and the solvent is then removed. The resulting oil is dissolved in refluxing acetonitrile and is then treated with carbon black. The desired product crystallizes on cooling. It is recrystallized from isopropanol. It melts at 134 C., using Thieles tube.

the enantiomorphs may be prepared. Thus, in particular, were prepared the optically active forms of compounds (I) wherein R is methyl and phenyl, respectively, and NR R is a 4-methylpiperazinyl radical. These compounds have melting points of 150 and 163 C., respectively, and optical rotation [od of 12.5 and 18.7, respectively, in ethanol solution.

In Table II below are set forth the characteristics of the triazines prepared in Examples 1-5 above, and of other triazines prepared in a similar manner.

In each space are indicated the melting point of the product and a code number thereof, consisting of symbols LA followed by a number; whenever necessary HCl or H O are mentioned in parentheses when the product was prepared as the hydrochloride or as a hydrate.

Analysis.Calculated (percent): C, 60.73; H, 7.65; O, TABLE II 5.06; N, 26.56. Found (percent): C, 60.71; H, 8.01; O, R H H H 5.16; N, 26.65. Diethylumr- Dimeth lami- The NMR spectrum 1s consistent with the structure. R Allyl noethyl 03m EXAMPLE 4 R 2) Hydrogen 146 148 2-am1no-4-allylam1no-6-a-hydroxy(4 -methoxy)- LA 1787 Methyl L 3 1% From 9 g. of allyldlguamde hydrochlonde, 10.5 g. of ethyl p-methoxymandelate, 50 ml. of 2 N methanol solu- Ethyl 5 86-87 83-85 88-00 tion of sodium methoxide and 40 ml. of methanol are l LA 1655 LA 1803 LA 1819 prepared, using a procedure similar to that of Example 6 31F131 3, 3.3 g. of product melting at 162 c. using Thieles tube. EE?) LA Analysis.--Calculated (percent): C, 58.62; H, 5.96; O, IOHOG 75 9H9 11.14; 11:, 24.38. Found (percent): C, 58.58; H, 6.13; O, y LA 1631 LA 1789 LA 5 11.28; 24.30.

2 5 2 The NMR spectrum is cons1stent w1th the structure. Phenyl fi f 2 32 LA EXAMPLE 5 p-Fluorophenyl 2 3% 2-amino-4-u-hydroxy (3 '-methoxy -benzyl- 40 136 6-(4methyl)-piperazinyl-1,3,5-triazine p-Chlorophen l LA 3 1 From 12.7 g. of 1-diguanyl-4-methyl-piperazine di-hy- Bmmo he 1 drochloride, 10.5 g. of ethyl m-methoxymandelate, ml. p p y LA 1770 of 2 N methanol solution of sodium methoxide and 40 ml. 7 138.139

o-Cl11o10pheuyl of methanol are prepared, using a procedure s1m1lar to 4 LA 1780 LA 1841 that of Example 3, 3.3 g. of product melting at C. 136438 m-Fluoro hen l usmg Thleles tube. p y LA 1801 Analysis.-Calculated (percent): C, 58.16; H, 6.71; 0, 1 H H H H 2 Found (p U- 58-01, 6,32, 0, r0 wimethyb Dibutymmb Dipmpykmm N: v 0 aminonopropyl nopropyl The NMR spectrum 15 conslstent with the structure. -P PY The compounds (I) prepared in Examples 1-5 are 141-142 98-09 108-110 racem c compounds. However, starting from optlcally ac R pheny1 LA 1813 LA 1821 LA 1836 t1ve acid der1vat1ves such as:

TABLE II-Coutiuued R1 Methyl Ethyl H Methyl H H H H R? Dimethyla- Dimethyla- Dimethyla- Diethylami- Dimethylal-dimethylaminoethyl minoethyl Cyclohexyl minopropyl Allyl noethyl minopropyl mine-2i PIOPY 101-103 128 136 170-172 p'Methyl Phenyl LA 178;]; LA 1711 LA 1701 101-10 ps pr py p y LA 1776 j l l 0 132-131 177-179 P'MethmY P LA 1 072 M 1 8 LA 1 LA 1190 9 -9 139-110 m'MethOXY Phenyl ---1 LA 1032 LA 1751 1 LA 1819 LA 1771 m-Trifiuoro methyl-phenyl 5 1%;

124-126 73-75 90-100 Ethyl L111 815 LA 1816 i 3,4-dichl0r0-phe11y1. L2 3 120-130 129-131 I -0 v p r LA 25 fifi zg 3,4, ,-tr t 0 v-p v LA 171,5 LA 3,4-rnethyleuedioxy-phenyl 136 g 1 Deeomposed.

2 Base.

TABLE H Cmi"ued triazines (I) and their action on the central nervous sysl H H H Methyl tem which insures a control of emotional disturbances, of

a v a the behavior and of the vegetative nervous system. B {$323 Determination of the toxic dosage in animals shows p w 5 the enormous therapeutical range of these triazines since a dosage of 500 mg./kg. of body weight must almost al- Ethyi {%i-g LL 1814 Ways be used to arrive at the lower limit of the LD in the series. Many examples are given below. y --{LA 7 104-100 108-100 01-03 Phony "{LA 1703 {LA 1783 LA 1817 10 Rats p-Chloro phenyl flgggg Oral LD50, Lp. LD50, Oral LD50, LD- L so, LV- L su, Products mg./kg. mg./kg. mgJkg. mg./kg. mgJkg. 120-133 100 107 166-l68 p-Methyl phenyl LA 1804 LA 1743 m-Methoxy {103-104 phcnyl LA 1791 3, 4, 5-trim0thoxy phenyl 3, 4-1nothyl- {101-105 115-117 150-151 enedioxy-phenyl LA 1758 LA 1788 LA 1748 103-104 123-125 Rqwyl "{LA 1750 LA 1824 153-155 100-103 155-150 "{LA 1842 LA 1033 LA 1753 i p-Fluoro phenyl p-Chloro phenyl G32 1822 NRR2 4-isopropyl 4-methyl 4-propyl 4-(2-hydr0xy piperazinyl pipcrapipcraethyl)- zinyl zinyl piperazinyl Hydwgc --{LA 1087 L1 11 777 i1 150 11 -1 0 Mflhy] "{LA 1688 LA 1708 EM 1 100-110 132 110-117 110-117 --{LA 1800 LA 1703 LA 1755 LA 1805 1 {118-120 IOPY LA1702 280 --i 2 1101,) LA 1'00 152-15 4 35 LA 1740 y "{2 0 2 LA 1080 72-73 8687 1 270 LA 1779 LA 1834 21101) 270 n-Nonyl (2 H01) A1707 n-Tctradccyl "$12155 ,1 {140-151 103 158 102 --1LA 1750 LA 1003 LA 1773 LA 1823 128 120 1 IPFIUOWDIIOIWL LA 7 LA 7 2 1 141-143 8 1 l wp y --{LA 1692 LA 792 1 p-B romopheuyl m-Fluoropllenyl 147-148 133-134 153-155 ll'hmhylphwyl "'{LA 1074 LA 1774 LA 1754 m-Chlorophenyl NR R, 4-allyl- 4-1110tl1yl- 4-propyl- 4-(2hypiperuzipipcrazipipcrazrdroxynyl nyl nyl otl1yl prperazlp-Isopropyl 1111011171 A 1695 121-122 102 1127- Phmyl --{LA1840 LA 1000 --1LA 1707 Chrome toxicity tests earned out 1n rats by daily oral 111-111011108 phonyl 2 1705 administration, during a period of time of three months, m-Trifiuoromothyl {103-105 -172 at dosages such as 10, 50 and 250 mg./kg., have shown,

vlwnyl- LA 17% 1135,9 in particular with products LA 1574, LA 1075, LA 1689, 2141110111010'Phcnyl "{LA1709 LA 1092, LA 1593, LA 1703, LA 1705, LA 1778, LA 3,4-dichloro-phenyl "$3123 1793, LA 1798, the absence of evidence of toxicity both 3 4 dimthoxy phenyl {105 from the standpoint of the clinical and biological observag3 1691 tion of the test animals and from the standpoint of the 3' g i g "i gififiiggi macroscopical and microscopical anatomical examination 4-1n0 1y enc loxy- 1 phcnyl. {LA 1808 LA 1008 LA 1778 LA 1845 of all Organs and W I cyclolmyl 169 The pharmacologlcal lnvestrgatron has shown that 1t 1s 16H67 70 particularly in the animal rendered abnormal by the m'muom phmyl 1769J action of drugs that triazines (I) have an action on the central nervous system, whereas triazines (I) show little activity in the normal animal. This is obviously of considerable interest. A table summarizing the essential results obtained in each test is given below.

3,703,514 9 Wlth apomorphine, vomiting in dog, restlessness and chewing in rat, are antagonized with certain derivatives, while restlessness in rat is potentiated with other derivatlVCS.

Apomorphine dosage, Dosage, Products lug/kg. Animal Route Restlessness Vomiting or chewing mg./kg.

25 Decrease 25 Complete protection. 10 .do-. Decrease 25 Increased. 50 10 O 50 Complete protection. 25 Decrease 25 25 5 Complete protection. 5 Strongly decreased. 50 Complete protection. 25 D ecreased Increase 10 Complete protection. 25 Increased. Decrease 10 Decreased 50 Complete protection" 50 Increased 10 Strongly decreased.. 1 Decreased 50 25 50 1O Decreased 50 do.- 50 do.. 50 ..do. 50 Increased. 10 ..d 0...... 50 Decreased....- Slight decrease 50 Highly increase Increase 50 Increased .-do 50 Complete protectlon Complete protection.. 50 Increased Decrease 10 o. Increase... 5 at Strongly decrease Decrease 25 11111806--.. 2I.P Rat I.P Complete protection ..do 25 NOTE. +=non-antagonized action; S.C.=sub-cutaneous.

With amphetamlne, m rat, restlessness and chewmg were antagonized s1mu1taneously or separately.

Ampheta- Am hetmme again; dosage dosage J Dosage, (mg /k Dosage, Products I.P.) Death rate mg./kg. Route etlesnesChwin P d ts I R s s s e 1; mg Ike R ut Decreased 1 Oral. LA 1655 10 Decreased... Decrease-. 50 8.0. 15 LA1674 15 0---" 50 S0. LA 1689 15 50 8.0. 0 LA 1692 12 50 s.0. 0.1 P LA 1693 10 50 S.C. 50 Ow LA 1703 12 8.0. 10 LP. LA 1706 15 10 s.0. Antaeomzed 1 LA 1707 15 50 s,c Decreased 0.1 LP. LA 1709 15 50 s.c. 15 0 LR LA 1743 10 Delayed.... 3.0. 15 l0 LA1746 10 Decreased.-. Decrease.. 8.0. 15 LA 1755 15 20 8,0, 15 .....do 10 Oral. LA 1763 10 50 S1), 15 Strongly decreased 10 LP. LA1773 10 50 3,0, 15 Antagonized 1 LP. A1775 15 10 s,c 15 Decreased 1 Oral. LA1787 20 S0. 5 10 LA 1792 20 so. 1 O LA1800 50 5.0. .",410 0.1 11- A 1 03 20 s1), 15 Sllghtly decreased 1 Oral. LA 1814 Decrease-- 25 8.0. 15 D ased 1 D0- LA 1822 15 .-do..... 20 3.0. 15 d 0 D LA 1824 10 Decreased -.do s.0. 20 t o yde e e 10 12 gntagonlged 1 gal. i 5 i n. ecrease NOTE 0 antagomzedact1on,+ non antago z daeto 15 00 10 $5 15 ..-do 10 In mzce, group toxicity tends to decrease. 25 Antagonized 8% fi 15 0 15 Decreased 10 Oral. Ampheta- 15 do 10 Do. mine 15 .-..do 25 Do. dosage 15 Strongly decreased 10 LP. (mg/kg. Dosage, 15 Decreased 1 LP. Products LP.) Death rate rug/kg. Route 5 052 hial 15 Decreased Oral. 1 Oral. 15 .--.-d 25 D0. 10 Do.

1 LP. .-...do 0.1 LP. 50 LP. Complete protection. 1 LP. 50 LP. 15 Decreased 25 Oral. 0.1 LP. 15 o 1 LP. LP.

With pentobarbital, sleep in mice was potentiated by many derivatives. Pentobarbital is administered intraperitoneally at a dosage of 30 mg./kg.

With tremorine, antagonism in mice begins at different dosages, according to the derivatives; the minimum active dose in the series was 1 mg./kg. by the oral route. Tremorine was administered intraperitoneally at a dosage Number olmice loosing Of 20 mg./kg.

the straightening-up reflex- Antagonism Out of Out oi 10 reference treated Dosage, Lac- Du- Products Route animals animals mg./kg. Trcm- Diar- Salivarimaration, Dose,

7 50 10 Products bling rhea tion tion min. mgJkg. Route 1 O 4 10 LA 1636.. O 0 O O 75 50 Oral. 0 4 50 LA 1665.. O O O 120 100 .P. 0 7 50 LA 1688.. O 45 50 LP. 0 4 50 LA 1694.. O 0 120 50 LP. 1 3 50 LA1695.. O O O O 30 50 LP. 0 4 10 LA 1607-. O 90 50 LP. 0 6 50 LA 1698.. O O O O 360 100 Oral. 0 5 50 LA 1698 O O O O 120 50 LP. 0 3 50 L'\1703.. O O O 60 50 LP. 1 6 LA 1703.. O O O O 90 50 LP. 0 5 50 LA 1709.. O O O O 75 50 Oral. 0 4 100 LA17-13 O O O O 60 50 .P. 0 4 20 LA 1746 O O O 30 50 Oral. 1 5 20 LA 175%.. O O O O 120 50 Do. 1 o 50 20 LA 1758.. 0 0 0 0 120 10 1.1. 1 6 100 LA1758.. O O O O 30 10 Oral. 1 7 10 LA 1762.- O O O O 120 50 D0. 1 3 50 LA 1763-- O O 0 O 30 50 Do 1 5 50 LA 1763.. O O O O 30 50 LP. 0 5 50 LA 1772.. O O O O 75 50 LP. 0 A 50 LA 1778.- O O O O 120 10 Oral. 0 5 50 5 LA 1778.- O O O O 120 1 LP. 0 4 100 LA 1782.- O O O O 120 50 LP. 2 6 50 LA 1788.. O O O O 60 Oral. 0 3 20 LA 1791.. O O O 50 D0. 2 5 20 LA 1794.- O 120 60 D0. 0 6 50 LA 1795.. O O O 60 50 D0. 0 5 20 LA 1798.. O O O O 120 50 Do. 0 3 50 LA1798- O O O O 60 10 LP. 2 7 50 30 LA 1803.- 0 0 0 0 so 50 Oral. 8 g LA 1804.-- O 120 50 Do. 0 4 0 N o'rE.-O=antag0nizcd action; +=non-antagonized action.

With reserpine, adminlstered intraperitoneally in mice The P Induced y a hot-111ate In KJ of 111166 at 2 nag/kg. hypothermia 1s potentiated or antagonized; 1S the flctlve dose, for y del'watlves, 136mg some derivatives antagonize also reserpine induced ptosis, 1658 t gy the Oral Ollie, Wlth a lower llmlt catalepsy and diarrhea. of l mg./kg. by the oral route. On the other hand, other Dose, Products Hypothermia Ptosis Catalepsy Diarrhea lug/kg. Route LA 1633 Potentiation 20 Oral.

50 L1. 50 LP. 20 Oral. 50 Oral. 50 LP. 50 Oral. 25 LP. 50 LP. 50 Oral. LP. 50 LP. 50 50 Decreased...{ Oral. Antagonism .d0 Decreased .do 53 25 Oral. Potentiatlon ..do 50 LR 50 LP. 25 LP.

Antagonism 50 Oral. Decreased" 50 LP. 50 LP. 50 LP. 50 Oral. Antagonism O 50 Do. Decreased ib? 60 LP. 25 LP. 50 Oral. 20 D0. 25 Do. 20 Do. 50 LP. Antagonism O 50 Oral. ....do Decreased 100 Do. ....do d 50 LP. Potentiation 20 Oral. Antagonism 50 Do. 25 Do.

50 LP. 50 LP. Anta onism 10 LP. ..do 100 Oral. Antagonism 50 LP. Decrcased 50 LP. LA 1823 .d0 50 LP.

N 0TE.O =antagonized action; =non-antagonized action; =undetcrmine.

Variation of reaction time to pain, percent Dose,

a-I e. oral route Products Increase Decrease When using compounds (I) against the action of nicotine administered in mice at a dosage of 1 mg./kg. by rapid intra-venous route, a protection against convulsive fits and death rate is frequently obtained; sometimes, in contrast, potentiation is obtained.

Dose,

Products Convulsions Death rate kg.

LA 1674-.. Complete protection.. Decreased 20 LA 1689 do Complete protection.. 10 LA 1693 do do 50 LA 1695 Potentiation Potentiation 20 LA 1703-. Complete protection. Complete protection- 20 LA 1706 do Decreased 20 Complete protection- 20 Decreased 20 -do...-. 20 LA 1750 Potentiation Potentiation 20 LA 1752- Complete protection- Complete protection- 20 LA 1766. Potentiation Potentiation 20 LA 1767 Protection 20 LA 1768. Potentiation 20 LA 1778 Protection. 20 LA 1781 Potentiation 20 LA 1784 do 20 LA 1803 Protection. 20 LA 1814 Potentiation 20 LA 1822- Complete protection- Complete protection. 80 LA 1823 Potentiation Potentiation 20 When compounds (I) are used against the sleep-inducing action of chloral administered intra-peritoneally in mice at a dosage of 300 mg./kg., the time-to-sleep and the duration of sleep are modified.

Dose I.P.,

Products Time-to-sleep Duration of sleep mgJkg.

LA 1674 Extended. Shortened 20 LA 1689. ---do 20 LA 1693 .do... ten 20 LA 1697 Shortened. 20 LA 1704. Extended.- Extended- 20 LA 1707 Shortened. Highly extended- 20 LA 1749 .do... Extended 20 LA 1750. ..-.-do.- 20 LA 1755 Extended 2 LA 1756 Shortened Extended 20 LA 1757. d 20 LA 1759- 20 LA 1762 do 20 LA 1763 20 LA 1764- 20 LA 1779 20 LA 1782 20 LA 1784- 20 LA 1791 Extended 20 LA 1800 Shortened 20 LA 1803- Extended 20 LA 1806 Slightly shortened ..do.. 20 LA 1808 Shortene 20 LA 1815 .do. 20 LA 1822 Extend 20 A 1823. ...do. 20

The convulsions induced in mice on rapid intravenous injection of pentamethylene tetrazol were decreased by certain compounds (I), particularly by LA 1697 at the dosage of 10 mg./kg., administered by the intraperitoneal route.

The pharmacological action in the normal animal shows the absence of behaviour disturbances in the absence of any associated medication.

No change in the performances to the traction test and to the test of the spinning rod at oral dosages of up to mg./kg. in mice, for the greater majority of the compounds.

In nembutal-anesthetized cat, minimal contraction of the nictitating membrane was found with some derivatives, for example with LA 1674, at an intravenous dosage of 5 mg./kg., the contraction has an intensity equivalent to that induced by 2 'y/kg. of adrenalin administered by the intravenous route.

In rat, guinea-pig, cat and dog anesthetized either with urethane or with nembutal, bradycardia of the sinus was found to occur with the following derivatives: LA 1674, LA 1689, LA 1692, LA 1693, LA 1695, LA 1698, LA 1705, LA 1760, LA 1760, LA 1763, LA 1784, LA 1793. (-For example, with LA 1793, cardiac frequency is decreased by an average of 15% at a dosage of 5 rug/kg. administered intravenously in dog.)

Changes of digitanin type are found to appear in the electrocardiogram from an intravenous dosage of 5 mg./kg.: cupuliform depression of the terminal stage and, at higher dosages: extension of auriculo-ventricular and intra-ventricular conduction in particular with LA 1692, LA 1693.

In rat, in a waking free condition, according to the individuals and according to the derivatives, systolic arterial pressure does not vary, or exhibits a variation of :2 cm. of mercury at oral dosages of 50 mg./kg.

In rabbit, undergoing respiratory depression induced by 25 mg./kg. of morphine, some derivatives have resulted in a substantial improvement of pulmonary ventilation (LA 1674, LA 1692, LA 1693, LA 1784, LA 1793).

In rabbit, in a waking condition, the cortical electroencephalogram exhibits perturbations at minimum dosages such as 1 to 5 mg./kg. administered intravenously, said modifications lasting one or two hours and being reproducible when the product is administered by the oral route. This was noted in particular with the following derivatives: LA 1674, LA 1689, LA 1693, LA 1703, LA 1705, LA 1707.

On the isolated duodenum of rat, compounds (-I) have antagonized the acetylcholine induced contraction and/or the barium chloride induced contraction, thus exhibiting an atropine-like or papaverine-like action in the ratios indicated in the following table:

Comparative action with- Products Atropine Papaverine Inflammation tests, either as first stage inflammation with carrageenin or as second stage inflammation on inclusion of filter-paper discs, were not influenced, in particular with LA 1703.

It is therefore apparent that compounds (I) have high therapeutical value, since they possess predominantly psychotropic properties which are reflected in at least one of the following activities:

they are active on activity and activometry, increasing same at low dosages and reducing it as high dosages;

on the electroencephalogram, they produce, in bursts,

either peaks or slow waves;

they decrease or cancel the group toxicity of amphetamine;

some have an antagonistic effect with respect to reserpine from the standpoint of the central and peripheral effects of the latter; others, in contrast, act in the same direction as reserpine;

they are extremely active anti-tremorine agents active at low dosages and by the oral route;

they are efficient oral analgesic agents;

they are inhibitors of )8 sympathetic receptors;

they have an influence on the action of apomorphine and on phenothiazine-induced catatonia;

they act on the cardio-respiratory system as analeptic and bradycardia-inducing agents, which makes them highly advantageous over the presently used neuroleptic or antidepressive agents.

The clinical applications were found consistent with what had been predicted from pharmacological experimentation.

Generally, different and frequently opposite activities are produced at low and high dosages. Similarly, the applications are not identical: minimum dosages are rather applicable to neuroses and higher dosages to psychoses; this explains the ver broad spectrum of useful dosages.

The triazines according to the invention act on the central nervous system: thus:

(a) LA 1689 was found efficient as anxiolytic and antidepressive agent at daily dosages varying from 2 to 1000 mg., according to the desired effects;

(b) LA 1692 and LA 1693, at daily dosages of from 5 to 850 mg. exhibit stimulating, anti-hallucinatory and antidepressive properties;

(0) LA 1763 and LA 1781, at daily dosages of 25 to 750 mg., have cured endogenous depressions;

(d) LA 1778, LA 1693 and LA 1798, at daily dosages of from 15 to 500 mg., have been found active against motor trembling;

(e) LA 1703, LA 1755 and LA 1803, at dosages of from 2 to 900 mg./kg., were found effective, according to the dosage, in a broad spectrum of anguish-type neuroses and of manic-depressive and hallucinatory psychoses;

(f) LA 1692, LA 1693 and LA 1784, at daily dosages of from 100 to 1000 mg. have produced a measurable stimulation of respiration together with a slowing down of the heart. These triazines have therapeutical usefulness in respiratory difiiculties and as cardio-circulatory analeptic agents.

In cases of general anesthesia, triazines (I) have increased respiration, facilitated awakening and decreased the sequelae of the anesthesia.

In cases of cardiac insufficiency, triazines (I), at the same dosage levels, slowed down the heart and improved cardiac compensation.

LA 1762 was found effective as a modulating agent of the adrenal gland.

Triazines (I) are free from hematologic, renal or hepatic toxicity at clinically useful dosages,

The therapeutically preferable triazines are presently: LA 1674, LA 1689, LA 1692, LA 1693, LA 1703, LA 1750, LA 1755, LA 1762, LA 1778, LA 1793, LA 1798, LA 1803, LA 1814, LA 1815, LA 1816, LA 1822, and LA 1837.

Triazines (I) may be administered in the form of capsules, tablets, syrup, granules, coated tablets with the excipients and vehicles suitable for the routes of administration adapted to such pharmaceutical forms.

Triazines (I) may also be administered in the form of suppositories and of intramuscular or intra-venous injection, either dissolved or dispersed in a suitable solvent, or bound with a delaying vehicle.

Generally, the dosage varies from about 2 to about 1000 mg. of active principle per 24 hours, each unit dose containing about 1-500 mg. of active principle.

It results from the above data that triazines (I) are free from toxicity and as have with a very broad spectrum of activity on the central nervous system, thereby permitting important new therapeutical applications in neuro-psychiatry and in the field of respiratory and cardiac reanimatron.

Having now described our invention what we claim as new and desire to secure by Letters Patent is:

1. A compound selected from the group consisting of a triazine of the formula:

wherein R is selected from the group consisting of hydrogen, lower alkyl, methylene-dioxy-phenyl, phenyl, phenyl monosubstituted with a substituent selected from halogen, lower alkyl, halo-lower alkyl and lower alkoxy, phenyl disubstituted with substituents selected from halogen, lower alkyl, halo-lower alkyl and lower alkoxy and phenyl tri-substituted with substituents selected from halogen, lower alkyl, halo-lower alkyl and lower alkoxy, R and R are selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, cyclo-lower alkyl, dilower alkylamino-lower alkyl, piperidino-lower alkyl and morphoino-lower alkyl, one of substituents R and R being other than a member selected from hydrogen and alkyl when the other substituent is itself a member selected from hydrogen and alkyl and the pharmaceutically acceptable acid addition salts thereof.

2. 2 amino-4-a-hydroxy-n-propyl-6-diethylaminoethylamino-1,3,5-triazine.

3. 2 amino 4-a-hydroxy-n-propyl-6-(N-methyl-N-dimethylaminoethyl)-amino-1,3,5-triazine.

References Cited UNITED STATES PATENTS 3,086,855 4/1963 Knusli et al. 260249.9 X 3,152,181 10/1964 Shapiro et al. 260249.9 X 3,169,964 2/1965 Calderbank et a1. 260249.9 3,522,255 7/1970 Heimberger 260249.9 3,583,986 6/1971 Heimberger 260249.9

JOHN M. FORD, Primary Examiner US Cl. X.R. 

